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NADPH oxidase restrains the matrix metalloproteinase activity of macrophages
Sean Y Kassim1, Xiaoyun Fu, W Conrad Liles
1Department of Medicine, University of Washington, Seattle, Washington 98195, USA.
Abstract:
Matrix metalloproteinases (MMPs) regulate numerous functions in normal and disease processes; thus, irreversibly blocking their activity is a key step in regulating MMP catalysis. We previously showed in vitro that oxidizing intermediates generated by phagocytes inactivate MMPs by modifying specific amino acids. To assess whether this mechanism operates in vivo, we focused on MMP-12, a macrophage-specific MMP known to mediate emphysema in mouse models. We found that mice lacking gp91(phox), a phagocyte-specific component of the NADPH oxidase, developed extensive, spontaneous emphysematous destruction of their peripheral air spaces, whereas mice deficient in both NADPH oxidase and MMP-12 were protected from spontaneous emphysema. Although gp91(phox)-null and wild-type macrophages produced equivalent levels of MMP-12 protein, the oxidant-deficient cells had greater MMP-12 activity than wild-type macrophages. These findings indicate that reactive intermediates provide a physiological mechanism to protect tissues from excessive macrophage-mediated damage during inflammation.
Insights
Oxidative intermediates generated by phagocytes inactivate matrix metalloproteinases (MMPs), preventing excessive tissue damage during inflammation. This mechanism protects against spontaneous emphysema in mice lacking NADPH oxidase.
Area of Science:
- Biochemistry
- Immunology
- Pathology
Background:
- Matrix metalloproteinases (MMPs) are crucial enzymes involved in various physiological and pathological processes.
- Irreversible inhibition of MMPs is a therapeutic strategy, but endogenous regulatory mechanisms are not fully understood.
- Phagocyte-derived oxidants can inactivate MMPs in vitro by modifying specific amino acids.
Purpose of the Study:
- To investigate the in vivo role of phagocyte-derived reactive intermediates in regulating matrix metalloproteinase-12 (MMP-12) activity.
- To determine if this oxidative inactivation mechanism protects against spontaneous emphysema mediated by MMP-12.
Main Methods:
- Utilized mouse models deficient in gp91(phox) (a component of NADPH oxidase) and MMP-12.
- Assessed spontaneous emphysema development in the lungs of these mouse models.
- Compared MMP-12 protein levels and activity in macrophages from wild-type and gp91(phox)-null mice.
Main Results:
- Mice lacking gp91(phox) exhibited spontaneous emphysematous destruction of air spaces.
- Mice deficient in both NADPH oxidase and MMP-12 were protected from spontaneous emphysema.
- Oxidant-deficient macrophages showed higher MMP-12 activity compared to wild-type macrophages, despite similar protein levels.
Conclusions:
- Reactive intermediates generated by phagocytes physiologically inactivate MMP-12.
- This mechanism serves as a protective measure against excessive macrophage-driven tissue damage during inflammation.
- Targeting this oxidative regulation could offer new therapeutic avenues for inflammatory lung diseases.
